RESUMO
Breast and gynecological cancers are major health concerns due to their increasing incidence rates, and in some cases, their low survival probability. In recent years, multiple compounds of natural origin have been analyzed as alternative treatments for this disease. For instance, Acetogenins are plant secondary metabolites from the Annonaceae family, and its potential anticancer activity has been reported against a wide range of cancer cells both in vitro and in vivo. Several studies have demonstrated promising results of Acetogenins' antitumor capacity, given their selective activity of cellular inhibition at low concentrations. This review outlines the origin, structure, and antineoplastic activities in vitro and in vivo of Acetogenins from Annonaceae against breast cancer and gynecological cancers reported to date. Here, we also provide a systematic summary of the activity and possible mechanisms of action of Acetogenins against these types of cancer and provide references for developing future therapies based on Acetogenins and nanotechnologies.
Assuntos
Acetogeninas , Annonaceae , Antineoplásicos Fitogênicos , Neoplasias da Mama , Neoplasias dos Genitais Femininos , Acetogeninas/farmacologia , Acetogeninas/química , Acetogeninas/isolamento & purificação , Humanos , Neoplasias da Mama/tratamento farmacológico , Feminino , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias dos Genitais Femininos/tratamento farmacológico , Annonaceae/química , Estrutura Molecular , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , AnimaisRESUMO
Given the importance of discovering plant species from the Brazilian Cerrado biome with anticancer potential, this study evaluated the antitumor activity of two extracts of Campomanesi adamantium fruits in in vitro and in vivo models of melanoma lung metastasis. Pulp and peel extracts (DEGPU and DEGPE, respectively) were extracted from fresh fruit using dichloromethane as a solvent. As cytotoxicity parameter, concentration values that inhibited 50% cell growth (GI50), total growth inhibition (TGI), and selectivity index (SI) were established. The melanoma lung metastasis model was obtained by injecting 5 × 105/50 µL B16-F10 cells via the tail vein of mice, which received treatment on the 15th day. Metastatic lungs were collected for fluorescence analysis with the IR-780 marker and also macro- and microscopic assessment. In vitro analyses showed that DEGPU was active in K562 (GI50 32.99; TGI 47.93) and U-251 (GI50 32.10; TGI 249.92), whereas DEGPE showed better cytotoxicity results for all tumor cell lines, but was more efficient in K562 (GI50 27.42; TGI 40.20) and U-251 (GI50 4.89; TGI 12.77). Both showed a cytocidal effect on B16F10 at the highest concentration tested, with approximately 25% (DEGPU) and 88% (DEGPE) of cell death. In vivo analyzes showed that both extracts showed significant activity in metastatic lung. Fluorescence images showed differences in intensity between groups owing to greater tumor involvement. Macro- and microscopic images showed that treatments with extracts limited tumor growth and prevented proliferation. The extracts tested have promising activity, thus requiring further research on their active compounds.
Assuntos
Antineoplásicos Fitogênicos , Proliferação de Células , Neoplasias Pulmonares , Myrtaceae , Extratos Vegetais , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Humanos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Myrtaceae/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Frutas/química , Camundongos Endogâmicos C57BL , Melanoma/tratamento farmacológico , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , BrasilRESUMO
O presente estudo teve como objetivo avaliar o efeito do extrato de Annona muricata no útero de camundongos fêmeas por meio de análises macro e microscópicas. Vinte camundongos fêmeas foram aleatoriamente distribuídas em quatro grupos: controle (solução salina), ciclofosfamida e extrato de folhas de graviola em duas concentrações diferentes (50 e 100mg/kg). Após sete dias de experimento, as fêmeas foram eutanasiadas e seus úteros coletados e submetidos a análise macroscópica, seguida de processamento histológico para análises morfológicas e morfométricas das camadas do útero e das glândulas endometriais. As características macroscópicas do útero foram mantidas em todos os grupos avaliados. Microscopicamente, não foram identificadas alterações patológicas nas células uterinas. No entanto, houve um aumento significativo na camada do miométrio após o tratamento com ciclofosfamida (p<0,05). O diâmetro interno das glândulas endometriais foi significativamente menor em ambos os grupos tratados com extrato de A. muricata quando comparados ao grupo controle (p<0,05), enquanto o diâmetro total das glândulas foi significativamente menor somente na maior concentração de extrato de A. muricata quando comparado ao grupo controle (p<0,05). A administração do extrato de folhas de A. muricata não causou alterações morfológicas ao útero. Desta forma, o extrato não apresentou toxicidade uterina nas condições avaliadas.
O presente estudo teve como objetivo avaliar o efeito do extrato de Annona muricata no útero de camundongos fêmeas por meio de análises macro e microscópicas. Vinte camundongos fêmeas foram aleatoriamente distribuídas em quatro grupos: controle (solução salina), ciclofosfamida e extrato de folhas de graviola em duas concentrações diferentes (50 e 100mg/kg). Após sete dias de experimento, as fêmeas foram eutanasiadas e seus úteros coletados e submetidos a análise macroscópica, seguida de processamento histológico para análises morfológicas e morfométricas das camadas do útero e das glândulas endometriais. As características macroscópicas do útero foram mantidas em todos os grupos avaliados. Microscopicamente, não foram identificadas alterações patológicas nas células uterinas. No entanto, houve um aumento significativo na camada do miométrio após o tratamento com ciclofosfamida (p<0,05). O diâmetro interno das glândulas endometriais foi significativamente menor em ambos os grupos tratados com extrato de A. muricata quando comparados ao grupo controle (p<0,05), enquanto o diâmetro total das glândulas foi significativamente menor somente na maior concentração de extrato de A. muricata quando comparado ao grupo controle (p<0,05). A administração do extrato de folhas de A. muricata não causou alterações morfológicas ao útero. Desta forma, o extrato não apresentou toxicidade uterina nas condições avaliadas.
Assuntos
Animais , Feminino , Camundongos , Útero/anatomia & histologia , Ciclofosfamida/administração & dosagem , Annona/química , Antineoplásicos Fitogênicos/uso terapêutico , Plantas Medicinais/química , Extratos Vegetais/uso terapêuticoRESUMO
Caesalpinia sappan and Haematoxylum brasiletto belong to the Fabaceae family, predominantly distributed in Southeast Asia and America. The isoflavonoid brazilin has been identified from the bark and heartwood of these plants. This review summarizes the studies describing the biological activities of these plants and brazilin. Mainly, brazilin protects cells from oxidative stress, shows anti-inflammatory and antibacterial properties, and hypoglycemic effect. In addition, it has a biological impact on various pathologies such as Alzheimer's disease, Parkinson's disease, fibrillogenesis, and osteoarthritis. Interestingly, most of the antecedents are related to the anticancer effect of brazilin. In several cancers such as osteosarcoma, neuroblastoma, multiple myeloma, glioblastoma, bladder, melanoma, breast, tongue, colon, cervical, head, and neck squamous cell carcinoma, brazilin induces autophagy by increasing the levels of the LC3-II protein. Furthermore, it inhibits cell proliferation and induces apoptosis through increased expression of Bcl-2, Bcl-XL, p21, p27, activation of caspase-3 and -7, and the cleavage of PARP and inhibiting the expression of Bax. In addition, it blocks the expression of JNK and regulates the nuclear translocation of Nrf2. Together, these data positions brazilin as a compound of natural origin with multiple bioactivities and therapeutic potential in various chronic degenerative diseases and cancer.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Benzopiranos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Doença Crônica , Etnofarmacologia , Fabaceae , Humanos , Medicina Tradicional , FitoterapiaRESUMO
Cervical cancer is the fourth leading cause of cancer mortality in women worldwide. Beetroot (Beta vulgaris L.) has bioactive compounds that can inhibit the progression of different types of cancer. To analyze the antiproliferative effects of beet leaf and root extracts, we performed MTT, clonogenic survival, cell cycle analysis, Annexin/PI labeling, and western blotting. Here, we report that 10 and 100 µg/ml of root and leaf extracts decreased cell viability and potentiated rapamycin and cisplatin effects while decreased the number of large colonies, especially at 10 µg/ml (293.6 of control vs. 200.0 of leaf extract, p = .0059; 138.6 of root extract, p = .0002). After 48 hr, 100 µg/ml of both extracts led to increased sub-G1 and G0/G1 populations. In accordance, 100 µg/ml of root extract induced early apoptosis (mean = 0.64 control vs. 1.56 root; p = .048) and decreased cell size (p < .0001). Both extracts decreased phosphorylation and expression of mechanistic Target of Rapamycin (mTOR) signaling, especially by inhibiting ribosomal protein S6 (S6) phosphorylation, increasing cleaved poly(ADP-ribose) polysomerase 1 (PARP1) and Bcl-2-like protein 11 (BIM), and decreasing cyclin D1 expression, which regulates cell cycle progression. Here, we demonstrate that beetroot and leaf extracts could be an efficient strategy against cervical cancer.
Assuntos
Antineoplásicos Fitogênicos , Beta vulgaris , Neoplasias do Colo do Útero , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose , Proliferação de Células , Células HeLa , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Oral cancer is a very common tumor worldwide with high incidence and mortality. The treatment of oral cancer involves surgery, radio- and chemotherapy; however, high failure rates and toxicity are noticed. Thus, the search of new drugs aiming a more effective treatment is welcomed. Natural products present chemopreventive and anti-cancer effects. Resveratrol is a naturally occurring antioxidant that contains several health benefits, including anti-inflammatory and antiproliferative activities. This review discusses the different action mechanisms of resveratrol related in the in vitro and in vivo studies using models of oral cancer.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Resveratrol/uso terapêutico , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Humanos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Resveratrol/metabolismo , Resveratrol/farmacologiaRESUMO
Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 µg/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NFκB specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Hydrocharitaceae , Morte Celular Imunogênica/efeitos dos fármacos , Neovascularização Patológica/patologia , Extratos Vegetais/uso terapêutico , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , Hydrocharitaceae/química , Morte Celular Imunogênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Anticancer activity of different phenols is documented, but underlying mechanisms remain elusive. Recently, we have shown that cannabidiol kills the cells of acute lymphoblastic leukemia (ALL) by a direct interaction with mitochondria, with their consequent dysfunction. In the present study, cytotoxic effects of several phenolic compounds against human the T-ALL cell line Jurkat were tested by means of resazurin-based metabolic assay. To unravel underlying mechanisms, mitochondrial membrane potential (∆Ψm) and [Ca2+]m measurements were undertaken, and reactive oxygen species generation and cell death were evaluated by flow cytometry. Three out of eight tested phenolics, cannabidiol, curcumin and quercetin, which displayed a significant cytotoxic effect, also dissipated the ∆Ψm and induced a significant [Ca2+]m increase, whereas inefficient phenols did not. Dissipation of the ∆Ψm by cannabidiol was prevented by cyclosporine A and reverted by Ru360, inhibitors of the permeation transition pore and mitochondrial Ca2+ uniporter, respectively. Ru360 prevented the phenol-induced [Ca2+]m rise, but neither cyclosporine A nor Ru360 affected the curcumin- and quercetin-induced ∆Ψm depolarization. Ru360 impeded the curcumin- and cannabidiol-induced cell death. Thus, all three phenols exert their antileukemic activity via mitochondrial Ca2+ overload, whereas curcumin and quercetin suppress the metabolism of leukemic cells by direct mitochondrial uncoupling.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Canabidiol/farmacologia , Curcumina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Quercetina/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Canabidiol/uso terapêutico , Curcumina/metabolismo , Curcumina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Jurkat , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Quercetina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
P2Et extract obtained from the Caesalpinia spinosa plant is abundant in phenolic compounds such as gallic acid and ethyl gallate and can generate signals to activate the immune response by inducing a mechanism known as immunogenic cell death in murine models of breast cancer and melanoma. Immunogenic cell death involves mechanisms such as autophagy, which can be modulated by various natural compounds, including phenolic compounds with a structure similar to those found in P2Et extract. Here, we determine the role of autophagy in apoptosis and the generation of immunogenic signals using murine wild-type B16-F10 melanoma cells and cells with beclin-1 gene knockout. We show that P2Et extract and ethyl gallate induced autophagy, partially protecting tumor cells from death and promoting calreticulin exposure and the release of ATP. Although ethyl gallate showed a mechanism similar to that of P2Et, the induction of apoptosis and immunogenic signals was significantly weaker. In contrast, gallic acid-induced autophagy acted by blocking autophagic flux, which was associated with increased cell death. However, this compound did not induce any of the immunogenic death signals evaluated. Therefore, the complex extract has greater antitumor potential than isolated compounds. Here, we show that inducing autophagic flux with P2Et protects cancer cells from cell death and that this delay in cell death is required for the generation of immunogenic signals.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Proteína Beclina-1/genética , Caesalpinia/química , Linhagem Celular Tumoral , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
Fruit plants have been widely used by the population as a source of food, income and in the treatment of various diseases due to their nutritional and pharmacological properties. The aim of this study was to review information from the most current research about the phytochemical composition, biological and toxicological properties of four fruit species widely used by the world population in order to support the safe medicinal use of these species and encourage further studies on their therapeutic properties. The reviewed species are: Talisia esculenta, Brosimum gaudichaudii, Genipa americana, and Bromelia antiacantha. The review presents the botanical description of these species, their geographical distribution, forms of use in popular medicine, phytochemical studies and molecules isolated from different plant organs. The description of the pharmacological mechanism of action of secondary metabolites isolated from these species was detailed and toxicity studies related to them were reviewed. The present study demonstrates the significant concentration of phenolic compounds in these species and their anti-inflammatory, anti-tumor, photosensitizing properties, among others. Such species provide important molecules with pharmacological activity that serve as raw materials for the development of new drugs, making further studies necessary to elucidate mechanisms of action not yet understood and prove the safety for use in humans.